SUBSTITUTED DIBENZ{8 a,h{9 AZULENONES AND 8-(OXA OR THIA) SUBSTITUTED DIBENZ{8 a,h{9 AZULENONES

ABSTRACT

Substituted dibenz(a,h)azulenones and 8-(oxa or thia) substituted dibenz(a,h)azulenones, e.g., 6,7-dihydrobenz(b)indeno(1,2-d)thiepin-8(8H)-one, prepared by treating a substituted spiro(1-benzoxa or thia-5(4H)-1&#39;&#39;-isobenzofuran)-3&#39;&#39;one with concentrated mineral acid. The compounds are useful as anti-depressants.

United States Patent Houlihan et al. 1 Aug. 29, 1972 [54] SUBSTITUTEDDIBENZla, h] [56] References Cited AZULENONES AND S-(OXA OR THIA)SUBSTITUTED DlBENZ 21, h] OTHER PUBLICATIONS AZULENONES Layton, ChemAbs. 55: 20615 10-1961).

[72] Inventors: William J. Houlihan, 15 Raynold Road, Mountain Lakes,NJ. 07046;

Jeffrey Nadelson, Troy Hills Village, 1480 Route 46, Parsippany, NJ.07054 Filed: May 14, 1970 Appl. No.: 37,342

US. Cl. ..260/327 B, 260/333, 260/340.5, 260/343.3, 260/559 R, 260/559S, 260/590,

Int. Cl ..A61k 27/00, C07d 67/00, C07d 9/00 Field of Search ..260/327 B,333, 340.5, 590

Primary Examiner-Henry R. Jiles Assistant Examiner-Cecilia M. ShurkoAttorney-Gerald D. Sharkin, Frederick H. -Weinfeldt, Robert S. Honor,Walter F. Jewell and Richard E. Vila ABSTRACT Substituteddibenz[a,h]azulenones and v8-(oxa or thia) substituteddibenz[a,h]azulenones, e.g.,6,7-dihydrobenz[b]indenod[1,2-d]thiepin-8(8l-l)-one, prepared bytreating a substituted spiro[l-benzoxa or thia-5(4l-l)-1'-isobenzofuran]-3-one with concentrated mineral acid. The compoundsare useful as anti-depressants.

4 Claims, No Drawings I SUBSTITUTED DIBENZMMMZULENONES 8-(0XA OR THIA)SUBSTITUTED DIBENZ[ AH] AZULENONES This invention relates todibenz['a,h]azulen'ones and 8-(oxaor thia')dibenz[a,h]azulenones-. Moreparticularly, it relates to substituted dibenz[a,h]azulenones and8'-(oxa or thia-)substituted dibenzEaJflazulbnones, intermediatesthereof and processes for their preparation.

R and R are independently, hydrogen, halo having an atomic weight of 19to 36, lower alkyl having one to four carbon atoms, e.g., methyl, ethyl,propyl, isopropyl, butyl, or isobutyl or lower alkoxy having one tofourcarbon atoms, e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy orisobutoxy;

R andR or R, and R or R and R together are .methylenedioxy;

R, and R or R and R or R and R together are The compounds of thisinvention may be represented 1'0' methylenedioxy; by thefollowingstruct'ural formula: x is p S or 0;

provided that 1. maximum number of substituents on ring Aand/or D istwo, and 2. there are no adjacent trifluoromethyl groups.

The process for preparing the compounds of formula (I) may berepresented by the following reaction scheme A. g (I) R8 R7 /X R7- /Xwherein R is hydrogen, halo having an atomic weight of 19 to 36, orlower alkoxy having one to four carbon atoms, ll R e.g., methoxy,ethoxy, propoxy, isopropoxy, butoxy or l 3 isobutoxy;

R and R are independently, hydrogen", lower alkyl (H) (I) having one tofour carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl orisobutyl, lower alkoxy having one to four carbon atoms, e.g., methoxy,ethoxy, wherein R R R R R R R R and X have the propoxy, isopropoxy,butoxy or isobutoxy, or trifluoromethyl',

R is hydrogen, halo having an atomic weight of 19 to 36, lower alkylhaving one to four carbon atoms, e.g., methyl, ethyl, propyl, isopropyl,butyl or isobutyl, lower alkoxy having one to four carbonatoms, e,g.,methoxy, ethoxy, propoxy, i sopropoxy, butoxy or isobutoxy, ortrifluoromethyl;

R and R are independently hydrogen, halo having 45 R8 H Li 1 X NCH3 R iRal.

above-stated significance. I

, The compounds offormula (I) are prepared by treatingv a compound offormula (II) with a concentrated mineral acid such as sulfuric acid orphosphoric acid, (sulfuric acid is preferred) at a temperature of fromabout "20 to 10 C. preferably from l0 to 0C. for

about 10 to 15 hours, preferably about 12 hours. The temperature usedare not critical. The compounds of formula (I) may be recovered usingconventional recovery techniques such as crystallization.

The compounds of formula (II) may be prepared by the following reactionscheme B:

adduet hydrolysis W) R. e I

I x R /X R,- 7

R5 R4 Ru- R4 l R5 H0 R3 R Rs O R R2 2 HN-C (H) 1 2 (III) 1H R1 1 awherein R R R R R R R R and X have the above-stated significance.

The compounds of formula (II) and formula (III) are prepared by treatinga compound of formula(V) with a compound of formula (IV) in the presenceof an inert gas, in an inert solvent such as diethyl ether,tetrahydrofuran, hexane, heptane, benzene and the like and subjectingthe reaction mixture to hydrolysis, preferably with aqueous ammoniumchloride. This is represented by reaction scheme b The reaction may becarried out at atemperature of from about 80 to 20 C., preferably 60 to-40 C. for about 1 to 3 hours. Compound (IV) is preferably added ininert solvent (as described above) to a cold (60 to 40 C.) inert solventsolution of compound (V). The solvents and the temperature used are notcritical. Compounds (II) may be separated from compounds (III) byconventional means such as filtration and/or crystallization.

Compounds (III) may be converted into compounds (II) by subjecting thereaction mixture of compounds (II) and (III) from scheme b in a solventas described in process b to a temperature of from 60 to the refluxtemperature of the solvent, preferably from 100 to 120 C. for to 48hours, preferably 24 hours. This is represented by reaction scheme bAlternatively compounds (III) may be separated (as described above) fromcompounds (II) and treated as described in scheme b Neither the solventsnor the temperatures used are critical. The compounds of formulas (II)and (111) may be recovered using conventional recovery techniques suchas crystallization.

Certain of the compounds of formula (V) are known and may be prepared bymethods disclosed in the literature, e. g., by the following reactionscheme C:

wherein R R R and R have the above-stated signifrcance and R is loweralkyl having 1 to 4 carbon atoms, e.g., methyl, ethyl, propyl,isopropyl, butyl or isobutyl.

The compounds of formula (V) are prepared by treating a compound offormula (VI) with an organo lithium compound of formula (VII) in aninert solvent (as described in reaction scheme b,) in the presence of aninert gas at a temperature of from about 10 to 10 C., preferably 5 to 5C. for about 1 to 3 hours. The solvents and the temperatures used arenot critical.

Certain of the compounds of formulas (IV), (VI) and (VII) are known andmay be prepared according to methods disclosed in the literature. Thosecompounds of formulas (IV), (VI) and (VII) not specifically disclosedare prepared according to analogous methods from known materials.

The compounds of formula (I) are useful because they possesspharmacological activity in animals. In particular, the compoundspossess central nervous system activity and can be used asanti-depressants as indicated by their activity in the mouse inreversing reserpine hypothermia (spencer, P.S.J., antagonism ofHypothermia in the Mouse by. Anti-depressants, in Anti-depressant Drugs,p. 194 204, Eds, S. Garattini and N.N.G. Dukes, Excerpta MedicaFoundation, 1967). I

The compounds may be administered orally or parenterally.

The dosage administered will vary depending on the particular compoundemployed, the therapy desired and the severity of the condition beingtreated. In general, satisfactory results are obtained when thecompounds are administered at a daily dosage of from about 1 30 mg/kg ofanimal body weight, preferably given in divided dosages, 2 to 4 times aday or in sustained release form. For most larger mammals (e.g.,primates) the total daily dosage is from about 20 milligrams to about100 milligrams. Dosage forms suitable for internal use comprise fromabout 5 milligrams to about 50 milligrams of the active compound inintimate admixture with a solid or liquid pharmaceutically acceptablecarrier or diluent.

A representative formulation suitable for oral administration is acapsule prepared by standard techniques which contain the following:

Ingredients Parts by Weight EXAMPLE I 6,7-dihydro-benz[b]indeno[ 1,2-d]thiepin-8(8H)- one Step 1 2,3-dihydro-spiro[l-benzothiepine-5-(4H)-l '-phthalan]-3-one and o-(2,3,4,5-tetrahydro-5-hydroxyl benzothiepin-S -yl) To a flask equipped with a stirrer,dropping funnel, condenser and gas inlet tube and maintained under anitrogen atmosphere there was added at room temperature 3.8 g (0.027mole) N-methyl benzamide and ml anhydrous tetrahydrofuran. The reactionflask was immersed in an ice bath and cooled to an internal temperatureof 5. Stirring was initiated and 38 ml of 15% n-butyl lithium (0.06mole) in hexane was added dropwise in about 40 minutes maintaining thetemperature below 8. The resulting N-methylbenzamide lithium adduct wasstirred at 5 for 1 hour longer and then the reaction flask was immersedin a dry-ice acetone bath and cooled to an internal temperature of -60.To the cold reaction mixture a solution of 5.35 g (0.03 mole) of3,4-dihydro-l-benzothiepin-5-(2l-I)-one in 30 ml anhydroustetrahydrofuran was added dropwise in about 30 minutes maintaining thetemperature between 60 to 5. The resulting adduct was stirred at 60 for1 hour and then allowed to warm to 0 in about 1 hour and then treatedwith 35 ml saturated ammonium chloride. The layers were separated andthe organic phase was washed once with 30 ml saturated ammoniumchloride, dried over anhydrous Mg SO and evaporated in vacuo. Theresulting oil was triturated with ether and the0-(2,3,4,S-tetrahydro-S-hydroxy-lbenzothiepin-S-yl)-N-methyl benzamide,mp 128 to l6. 2-[ 2,3,4,5-tetrahydro--hydroxy-6-methyll benzothiepin-S-y1 ]-N,3-dimethyl-benzamide Following the procedure of Example I, step2, and in place of 2,3-dihydro-spiro [l-benzothiepin-S-(4I-I)-lphthalan-3 -one, starting with the appropriate intermediate of formulaII of step 1 of this example, the following products are obtained:

1. 6,7-dihydro-8H-benz[b]indeno[ l ,2-d]oxepin-8- one 2.5,6-dihydro-dibenz[a,h]azulen-8(7H)-one 3. 6, 7-dihydro-ll-methyl-benz[b]indeno[1,2-d ]thiepin-8( 8l-I)-one 4. ll-chloro-6,7-dihydro-benz[b]indeno[ 1,2-d ]thiepin-8( 8H )-one 5.6,7dihydro-l l-methyl-benz[b]indeno[ l,2-d ]thiepin-8( 8I-l)-one 6.3-chloro6,7-dihydro-2-methoxy-benz[b]indeno[ l,2-d]thiepin-8-(8H)-one 7.6,7-dihydro-3-methoxy-2-methyl-benz[b]indeno[ l,2-d]thiepin-8(8H)-one 82-chloro-6,7 -dihydro-3-methyl-benz[b]indeno[ l,2-d]thiepin-8(8H)-one 9.6,7-dihydro-2,3-methylenedioxy-benz[b]indeno[ l,2-d]thiepin-8(8H)-onel0. 6,7-dihydrol O, l 2-bis trifluoromethyl-benz[ b] indeno[ l,2-d]thiepin-8( 8H)-one l l. 9-chloro-6,7-dihydro-ll-trifluoromethyl-benz [b]indeno[-d]thiepin-8(8H)-one l 2.l-chloro-6,7-dihydrol O-methyl-benz [b]indeno l ,2-d]thiepin-8(8H)-one l3. 4-chloro6,7-dihydrol 2-methoxy-benz[ b] indeno[ l,2-d]thiepin-8-(8H)-one 14. 6,7-dihydro-4-methyll O-methoxy-benz[b]indeno[1,2-d]thiepin-8( 8H)-one l 5. 6,7-dihydrol -methyl-9-methoxy-benz[b]indeno[ l ,2-d]thiepin-8( 8H)-one l6.6,7-dihydro-l2-methyl-benz[b]indeno[1,2-d ]thiepin-8( 8I-I)-one EXAMPLEIll This example describes the procedure for preparing compounds offormula I following the procedure of reaction schemes A, b,, b and C.The conditions of Example I, steps 1 and 2, are followed, with theexception that the compounds of the hydrolysis reaction mixture of step1 (Ex. I) are not separated but instead are refluxed in anhydroustetrahydrofuran to convert the intermediate of formula III into theintermediate of formula II.

Step 1 By using the conditions of Example I, step 1 and in place ofN-methyl-benzamide and 3,4-dihydro-lbenzothiepin-5-(2H)-one startingwith l 3 ,4-methylenedioxy-N-methylbenzamide 2. 3 ,4-dihydrol-benzoxaepin-5-( 2H )-one,

a reaction mixture of the following intermediates of formula II andformula III respectively are prepared:

1 2,3-dihydro-5 ,6-methylenedioxy-spiro[ 1- benzoxepin- 5(4H)-l-phthalan]-3 -one 2. 2-[2,3,4,5-tetrahydro-5-hydroxyl -benzoxepin-5- yl]-N-methyl-4,5-methylenedioxy-benzamide Step2 The reaction mixture ofstep 1 of this example is refluxed in anhydrous tetrahydrofuran, and theresulting 2,3-dihyrdo-5,6'-methylene-dioxy-spiro-[ l-benzox- 5epin-5(4H)-l'-phthalan]-3'-one is treated following the procedure ofExample I, step 2, to obtain the product, 6,7-dihydrol 0,1l-methylenedioxy benz[b]indenod[ l ,2-d]thiepin-8-(8H )-one.

What is claimed is:

wtherein R is hydrogen, halo having an atomic weight 19 to 36, or loweralkoxy having one to four carbon atoms;

R and R are independently hydrogen, lower alkyl having one to fourcarbon atoms, lower alkoxy having one to four carbon atoms ortrifluoromethyl;

R is hydrogen, halo, having an atomic weight of 19 to 36, lower alkylhaving one to four carbon atoms, lower alkoxy having one to four carbonatoms, or trifluoromethyl;

R and R are independently hydrogen, halo having an atomic weight of 19to 36, or lower alkyl having one to four carbon atoms;

R, and R are independently hydrogen, halo having an atomic weight of 19to 36, lower alkyl having one to four carbon atoms, or lower alkoxyhaving one to four carbon atoms;

R and R or R and R or R and R together are methylenedioxy; or

R and R or R, and R or R and R together are methylenedioxy; and X isCI-l S or 0;

provided that 1. maximum number of substituents on each of rings A and Dis two, and 2. there are no ad- 5 5 jacent tn'fiuromethyl groups.

2. The compound according to claim 1 which is 6,7-

dihydro-benzo[b]indeno[ l ,2-d]thiepin-8( 8H )-one.

3. The compound according to claim 1 which is 6,7-

dihydro-8H -benz[b]indeno[ l,2-d]oxepin-8-one.

4. The compound according to claim 1 which is 5,6-

dihydro-dibenz[a,h]azulen-8(7H)-one.

2. The compound according to claim 1 which is 6,7-dihydro-benzo(b)indeno(1,2-d)thiepin-8(8H)-one.
 3. The compound according to claim 1 which is 6,7-dihydro-8H -benz(b)indeno(1,2-d)oxepin-8-one.
 4. The compound according to claim 1 which is 5,6-dihydro-dibenz(a,h)azulen-8(7H)-one. 